Cell fate transition occurs under various developmental, physiological, and pathological conditions, including normal embryonic development, aging, and tissue regeneration as well as tumor initiation and progression. Defining the cellular and molecular mechanisms of cell fate transition and regulating these mechanisms may be an essential strategy for treating abnormal pathological conditions resulting from improper cell fate control. The recent development of induced pluripotent stem cell (iPSC) technology used to reprogram somatic cells into pluripotent stem cells using defined pluripotency factors allows us to more closely mimic and recapitualte the conditions of cell fate transition (see Takahashi K, et al., Cell, 2006, 126(4), 663-676).
Generally, complex molecular changes at genetic, epigenetic, and metabolic levels have occurred concurrently or sequentially during the stage of somatic cell reprogramming. Cell reprogramming faces the challenge of balancing stability and plasticity and must overcome critical barriers, such as cell cycle checkpoints, the mesenchymal-epithelial transition (MET), and metabolic reprogramming, to progress cell fate conversion from a stochastic early phase toward pluripotency (see Buganim Y, et al., Cell, 2012, 150(6), 1209-1222).
The p53 pathway limits cell fate transition by inducing classical signaling leading to cell cycle arrest, senescence, or apoptosis to protect genome stability against reprogramming-induced stress, and compromised p53 signaling accelerates the reprogramming process. Moreover, p53 governs the homeostasis of the cellular state, which constrains MET by repressing the Klf4-mediated expression of epithelial genes early in the reprogramming process, and which opposes glycolytic metabolic reprogramming.
Balancing mitochondrial dynamics is crucial for maintaining cellular homeostasis, and abnormal mitochondrial dynamics results in numerous diseases. Highly proliferative cells, such as iPSCs and tumor cells, prefer to undergo glycolysis and decrease the dependency on mitochondrial ATP production, which requires supporting the biosynthesis of macromolecules and alleviating mitochondrial oxidative stress in rapidly growing cells.